Deciphering the potential molecular network underlying nicotine- and its metabolite cotinine-induced myocardial infarction via network toxicology, molecular dynamics, and in vitro experimental validation
Abstract
Smoking is a major modifiable risk factor for myocardial infarction (MI); however, the molecular mechanisms through which its core component nicotine and its primary metabolite cotinine mediate MI development remain incompletely understood. This study aimed to identify key molecular targets and characterize the mechanistic basis by which nicotine and cotinine mediate myocardial injury relevant to MI. To this end, we performed two-sample Mendelian randomization using GWAS data for smoking (468,170 participants) and MI (20,197 cases, 440,906 controls) from the IEU Open GWAS Project to genetically validate the smoking-MI causal association. Potential targets of nicotine and cotinine were predicted from four databases (SEA, TargetNET, SwissTargetPrediction, ChEMBL). MI-related targets were retrieved from DisGeNET and GeneCards. Shared targets among nicotine, cotinine, and MI were identified, followed by PPI network analysis, GO/KEGG enrichment, and topological screening (MCC and Degree). Core targets were validated using GEO transcriptomic datasets (GSE113871, GSE115031). Molecular docking and 200-ns molecular dynamics simulations were performed to evaluate potential ligand-target interactions. In vitro CCK-8 and qRT-PCR assays in H9c2 cardiomyocytes assessed cytotoxicity and target expression. MR analysis confirmed a significant positive causal association between smoking and MI. We identified 44 shared targets, with ADRA2A validated as the key functional target. Molecular…
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